What is the optimal third-line therapy in unselected patients with stage IV inoperable NSCLC?

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Introduction

The majority of patients treated with NSCLC have stage IV disease, with common sites of metastases including lymph nodes, the pleura, liver, adrenal glands, bone and brain. Consequently, systemic therapy has been the mainstay of treatment attempting to control overall disease. A historical summary of the evolution of systemic drug treatment for stage IV NSCLC can be found here. The focus of the following question is based on the evidence in support of the old and new practice paradigms for stage IV NSCLC. Empirical therapy refers to therapy given to all fit patients deemed suitable without any particular restrictions.

Third-line therapy

Few randomised controlled trials (RCTs) have evaluated third line therapy in unselected patients with advanced NSCLC. The aforementioned negative RCT (ISEL) of gefitinib versus placebo in 1692 patients included 847 patients (50%) that had received two previous lines of therapy.[1] The positive RCT (BR21) of erlotinib versus placebo in 731 patients included approximately 50% of patients having received two previous lines of therapy. Univariate analysis of OS by number of prior regimens found OS remained in favour of erlotinib (compared with placebo) by similar magnitude to the overall study population results (HR 0.80, p = 0.02).[2] The study by Kim et al, comparing gefitinib to docetaxel in previously treated advanced NSCLC, only included 235 (16%) patients that had received two previous lines of therapy. Analysis of OS number of prior regimens found OS more in favour of docetaxel. But as this is a post hoc analysis with small patient numbers, it is not appropriate to draw conclusions.[3]

The Japanese DELTA study enrolled both 2nd and 3rd line patients, but only 17% of patients were 3rd line in this study.[4] In this study of 301 patients, PFS favoured docetaxel (median 2.9 vs 1.3 months, p=0.01), with no significant difference in overall survival (median 10.1 vs 9.0 months, p=0.91). With PD-1 or PD-L1 immunotherapy having been shown to be superior to docetaxel as 2nd line therapy (see immunotherapy section), the DELTA trial and other studies support the use of docetaxel as 3rd line therapy in fit patients.

Evidence summary and recommendations

Evidence summary Level References
In unselected previously treated patients with advanced NSCLC who have received two lines of therapy, single agent docetaxel administered 3 weekly is a potential option in fit patients.
Last reviewed September 2017
II [4]
Evidence-based recommendationQuestion mark transparent.png Grade
In fit, previously treated patients with advanced NSCLC who have received two lines of therapy, single agent docetaxel administered 3 weekly can be considered.
Last reviewed September 2017
B


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References

  1. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005 Oct;366(9496):1527-37 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16257339.
  2. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005 Jul 14;353(2):123-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16014882.
  3. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008 Nov 22;372(9652):1809-18 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19027483.
  4. 4.0 4.1 Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol 2014 Jun 20;32(18):1902-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24841974.

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Appendices

Further resources

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